The function of the visual system is to form images in the brain. Correct specification and patterning of the photoreceptor neurons within the retina are a prerequisite for precise retinotopic axonal projections and image formation. Many aspects of photoreceptor orientation and morphogenesis are generated through regulated cell adhesion behavior of individual neurons or groups of neurons. The Drosophila eye serves as a paradigm for most aspects of eye development, retinal biology and disease. The Drosophila retina is composed of a stereo-typed array of several hundred unit eyes, or ommatidia, each containing a precise arrangement of 8 photoreceptor neurons, which are oriented with respect to each other and also the whole retinal field and body axes. The establishment of this precise arrangement requires the interplay of several signaling pathways, transcription factors, and cell adhesion molecules. These are conserved and share equivalent functions in the mammalian eye. The correct specification of different photoreceptor subtypes requires an interplay of the Wnt/Frizzled-planar cell polarity (Fz-PCP), Egfr and Notch signaling pathways. A critical aspect that follows the cell fate specification is a cell adhesion/cell motility process called ommatidial rotation. It leads to a 90 degree rotation of clusters of photoreceptor precursors and places them in their proper position to allow subsequent photoreceptor morphogenesis. The scope of this application is to dissect the mechanistic regulatory interactions between the signaling pathways and the "executing" cell adhesion factors (and associated cytoskeletal elements). Based on our preliminary studies we hypothesize that the Nemo kinase (a MAPK family member) integrates regulatory input from Fz/PCP, Notch and receptor tyrosine kinase (RTK)/Ras signaling to itself regulate the behavior of several cell adhesion molecules and in particular the cadherin/catenin complexes. Strikingly, in all involved signaling pathways (Wnt/Fz-PCP, Notch and RTK/Ras) a novel non-canonical pathway branch is employed. The components of these cell adhesion specific signaling branches are only being discovered now, and thus an exciting new signaling network is emerging. We will use a combination of Drosophila in vivo studies and biochemical experiments to define the mechanistic regulatory interactions between the signaling components and the cell adhesion factors. In the human eye, Fz and Notch signaling are associated with many diseases, like Familial Exudative Vitreoretinopathy (FEVR) or Norrie Disease. Several components of the Wnt/Fz and Notch pathways are also critically linked to cancer and are associated with stem cell biology. Thus the information acquired in this application will advance our understanding of photoreceptor morphogenesis and eye diseases, and will also be of medical relevance in other areas, including stem cell biology and cancer. PUBLIC HEALTH RELEVANCE: RTK/Ras, Notch and Wnt/Fz-planar cell polarity signaling pathways have been implicated in many growth and patterning contexts, and are linked to many diseases, ranging from retinal degeneration and angiogenesis defects to cancer. This application addresses the regulatory input of these pathways that is specific to cell adhesion, motility and morphogenesis in the patterning of photoreceptor neurons and epithelial cells in general. The information acquired here will be of importance for several eye diseases and other medical disorders.